Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that form transmembrane, cation- permeable channels which open upon agonist binding. iGluRs are the major mediators of excitatory synaptic transmission in the central nervous system (CNS). The (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazole) propionic acid (AMPA) subtype of iGluRs (AMPAR) is essential for the fast excitatory neurotransmission in the CNS and expression and maintenance of long-term potentiation (LTP) that may underlie learning and memory. Malfunction of AMPAR has been implicated in several neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS), cognitive deficits, epilepsy, schizophrenia, and mood disorders. Therefore, an understanding of the structure and function relationships in AMPARs may lead to the development of valuable therapeutic agents. We believe that the extracellular amino-terminal domain (ATD) of AMPARs may be a target for potential non- competitive agonists/antagonists which modulate AMPAR channel activity in an allosteric manner. In comparison to the competitive drugs that directly target the neurotransmitter-binding site and disrupt the receptor's normal function in synaptic transmission, these non-competitive compounds are more desirable from a therapeutic perspective. We propose to take a structure-based drug discovery approach focusing on the AMPAR-ATD. The specific aims are: (1) Determine the high-resolution crystal structure of the AMPAR-ATD, and characterize the function of the AMPAR-ATD by structure-based mutagenesis and electrophysiology;(2) Identify and characterize the ATD-targeting allosteric modulators for AMPAR. The proposed studies will further our understanding of the regulatory mechanisms controlling channel activity of AMPARs, and identify potential drug candidates that target the AMPAR-ATD and allow us to fine-tune the activities of AMPAR. These non-competitive compounds will provide exciting promise for therapeutic use. PUBLIC HEALTH RELEVANCE: Malfunction of the AMPA subtype glutamate receptors (AMPARs) has been implicated in neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS), cognitive deficits, epilepsy, schizophrenia, and mood disorders. We propose to study the structure and function relationships in the extracellular amino-terminal domain (ATD) of AMPARs. We believe that the AMPAR-ATD may be a novel target for potential non-competitive modulators. These compounds modulate AMPAR channel activity in an allosteric manner and hold promise to be a new generation of therapeutic agents.